8,8a-dihydroindeno[1,2-d]thiazole derivatives which carry in the 2-position a substituent having a sulfonamide structure or sulfone structure; processes for their preparation and their use as medicaments

ABSTRACT

8,8a-Dihydroindeno[1,2-d]thiazole derivatives which carry in the 2-position a substituent having a sulfonamide structure or sulfone structure; processes for their preparation and their use as medicaments  
     The invention relates to polycyclic dihydrothiazoles and to their physiologically acceptable salts and physiologically functional derivatives.  
     Compounds of formula I,  
                 
 
     in which the radicals are as defined above, and their physiologically acceptable salts and processes for their preparation are described. The compounds are suitable, for example, as anorectics.

[0001] This application claims priority to German Application No.10009311.6 filed Feb. 26, 2000, the entire contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

[0002] The invention relates to polycyclic dihydrothiazoles and to theirphysiologically acceptable salts and physiologically functionalderivatives.

BACKGROUND OF THE INVENTION

[0003] Thiazolidine derivatives having anorectic action have beendescribed in the prior art (Austrian Patent No. 365181).

[0004] The object of the invention is to provide compounds having atherapeutically useful anorectic action.

SUMMARY OF THE INVENTION

[0005] The invention relates to compounds of formula I:

[0006] in which

[0007] R1, R1′ are independently selected from H, F, Cl, Br, I, CF₃,NO₂, CN, COOH, COO(C₁—C₆)-alkyl, CONH₂, CONH(C₁—C₆)-alkyl,CON[(C₁—C₆)-alkyl]₂, (C₁—C₆)-alkyl, (C₂—C₆)-alkenyl, (C₂—C₆)-alkynyl,O—(C₁—C₆)-alkyl,

[0008] wherein one or more of the hydrogens of the alkyl radicals may bereplaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH₃,OC(O)H, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂;

[0009] SO₂—NH₂, SO₂NH(C₁—C₆)-alkyl, SO₂N[(C₁—C₆)-alkyl]₂,S—(C₁—C₆)-alkyl, S—(CH₂)₂-phenyl, SO—(C₁—C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁—C₆)-alkyl, SO₂—(CH₂)_(n)-phenyl,

[0010] wherein n is 0-6 and the phenyl radical may be substituted up totwo times by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁—C₆)-alkyl,(C₁—C₆)-alkyl or NH₂;

[0011] NH₂, NH—(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂, NH(C₁—C₇)-acyl, phenyl,biphenylyl, O—(CH₂)_(n)-phenyl, where n is 0-6, 1- or 2-naphthyl, 2-, 3-or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl,

[0012] wherein any of the phenyl, biphenylyl, naphthyl, pyridyl, furanylor thienyl rings may be substituted one to three times by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂,NH(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂, SO₂—CH₃, COOH, COO—(C₁—C₆)-alkyl orCONH₂;

[0013] 1,2,3-triazol-5-yl, where the triazole ring may be substituted inthe 1-, 2- or 3-position by methyl or benzyl; or

[0014] tetrazol-5-yl, where the tetrazole ring may be substituted in the1- or 2-position by methyl or benzyl;

[0015] R2 is H, (C₁—C₆)-alkyl, (C₃—C₆)-cycloalkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl, (CH₂)n-furyl, C(O)—(C₁—C₆)-alkyl,C(O)—(C₃—C₆)-cycloalkyl, C(O)—(CH₂)_(n)-phenyl, C(O)—(CH₂)_(n)-thienyl,C(O)—(CH₂)_(n)-pyridyl or C(O)—(CH₂)_(n)-furyl,

[0016] wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl andfuryl may be substituted up to two times by Cl, F, CN, CF₃,(C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;

[0017] R3 is H, (C₁—C₆)-alkyl, F, CN, N₃, O—(C₁—C₆)-alkyl,(CH₂)_(n)-phenyl, (CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl,

[0018] wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl andfuryl may be substituted up to two times by Cl, F, CN, CF₃,(C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl; OC(O)CH₃, (C₂—C₆)-alkynyl,(C₂—C₆)-alkenyl, COO(C₁—C₆)-alkyl, C(O)OH, C(O)NH₂, C(O)NHCH₃ orC(O)N(CH₃)₂;

[0019] R4 is (CH₂)_(n)—R5, wherein n is 0-6;

[0020] R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl,2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or5-oxazolyl, 1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2- or3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,2-(1,3,5-triazinyl), 2- or 5-benzimidazolyl, 2-benzothiazolyl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl,indol-5-yl or N-methylimidazol-2-, -4- or -5-yl;

[0021] and R5 is substituted by

[0022] NH—SO₂—(C₁—C₆)-alkyl or NH—SO₂-phenyl,

[0023] wherein the phenyl ring may be substituted up to two times by F,Cl, CN, OH, (C₁—C₆)-alkyl, O—(C₁—C₆)-alkyl, CF₃, COOH, COO(C₁—C₆)-alkyl,CONH₂, (CH₂)_(n)—SO₂—(C₁—C₆)-alkyl, where n is 1-6, (CH₂)_(m)—SO₂—NH₂,(CH₂)_(m)—SO₂—NH—(C₁—C₆)-alkyl, (CH₂)_(m)—SO₂—N[(C₁—C₆)-alkyl]₂ or(CH₂)_(m)—SO₂—N(═CH—N(CH₃)₂), wherein m is 0-6;

[0024] and R5 may be further substituted by F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁—C₆)-alkyl, S—(C₁—C₆)-alkyl, SO—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl,(C₃—C₆)-cycloalkyl, COOH, COO(C₁—C₆)-alkyl, COO(C₃—C₆)-cycloalkyl,CONH₂, CONH(C₁—C₆)-alkyl, CON[(C₁—C₆)-alkyl]₂, CONH(C₃—C₆)-cycloalkyl,NH₂, NH—CO—(C₁—C₆)-alkyl, NH—CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl,piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,(CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl orSO₂—(CH₂)_(n)-phenyl, wherein n is 0-3;

[0025] and their physiologically acceptable salts and physiologicallyfunctional derivatives.

[0026] The invention also relates to pharmaceutical compositionscontaining the compounds of formula I and pharmaceutically acceptablecarriers. Also, pharmaceutical compositions containing the compounds offormula I in combination with at least one additional anorectic agentsare contemplated. The invention envisages treatment of obesity viaadministration of compounds of formula I. Methods of treatment for typeII diabetes and methods of enhancing lipid metabolism are alsocontemplated.

DETAILED DESCRIPTION OF THE INVENTION

[0027] The invention is directed to polycyclic thiazole compounds whichare anorectics and are useful in the treatment of type II diabetes andobesity. The compounds have general formula (I):

[0028] in which

[0029] R1, R1′ are independently selected from H, F, Cl, Br, I, CF₃,NO₂, CN, COOH, COO(C₁—C₆)-alkyl, CONH₂, CONH(C₁—C₆)-alkyl,CON[(C₁—C₆)-alkyl]₂, (C₁—C₆)-alkyl, (C₂—C₆)-alkenyl, (C₂—C₆)-alkynyl,O—(C₁—C₆)-alkyl,

[0030] wherein one or more of the hydrogens of the alkyl radicals may bereplaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH₃,OC(O)H, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂;

[0031] SO₂—NH₂, SO₂NH(C₁—C₆)-alkyl, SO₂N[(C₁—C₆)-alkyl]₂,S—(C₁—C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁—C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂—(C₁—C₆)-alkyl, SO₂—(CH₂)_(n)-phenyl,

[0032] wherein n is 0-6 and the phenyl radical may be substituted up totwo times by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁—C₆)-alkyl,(C₁—C₆)-alkyl or NH₂;

[0033] NH₂, NH—(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂, NH(C₁—C₇)-acyl, phenyl,biphenylyl, O—(CH₂)_(n)-phenyl, where n is 0-6, 1- or 2-naphthyl, 2-, 3-or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl,

[0034] wherein any of the phenyl, biphenylyl, naphthyl, pyridyl, furanylor thienyl rings may be substituted one to three times by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂,NH(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂, SO₂—CH₃, COOH, COO—(C₁—C₆)-alkyl orCONH₂;

[0035] 1,2,3-triazol-5-yl, where the triazole ring may be substituted inthe 1-, 2- or 3-position by methyl or benzyl; or

[0036] tetrazol-5-yl, where the tetrazole ring may be substituted in the1- or 2-position by methyl or benzyl;

[0037] R2 is H, (C₁—C₆)-alkyl, (C₃—C₆)-cycloalkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl,C(O)—(C₁—C₆)-alkyl, C(O)—(C₃—C₆)-cycloalkyl, C(O)—(CH₂)_(n)-phenyl,C(O)—(CH₂)_(n)-thienyl, C(O)—(CH₂)_(n)-pyridyl or C(O)—(CH₂)_(n)-furyl,

[0038] wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl andfuryl may be substituted up to two times by Cl, F, CN, CF₃,(C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;

[0039] R3 is H, (C₁—C₆)-alkyl, F, CN, N₃, O—(C₁—C₆)-alkyl,(CH₂)_(n)-phenyl, (CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl,

[0040] wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl andfuryl may be substituted up to two times by Cl, F, CN, CF₃,(C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;

[0041] OC(O)CH₃, (C₂—C₆)-alkynyl, (C₂—C₆)-alkenyl, COO(C₁—C₆)-alkyl,C(O)OH, C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂;

[0042] R4 is (CH₂)_(n)—R5, wherein n is 0-6;

[0043] R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl,2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or5-oxazolyl, 1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2- or3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,2-(1,3,5-triazinyl), 2- or 5-benzimidazolyl, 2-benzothiazolyl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl,indol-5-yl or N-methylimidazol-2-, -4- or -5-yl;

[0044] and R5 is substituted by NH—SO₂—(C₁—C₆)-alkyl or NH—SO₂-phenyl,

[0045] wherein the phenyl ring may be substituted up to two times by F,Cl, CN, OH, (C₁—C₆)-alkyl, O—(C₁—C₆)-alkyl, CF₃, COOH, COO(C₁—C₆)-alkyl,CONH₂, (CH₂)_(n)—SO₂—(C₁—C₆)-alkyl, where n is 1-6, (CH₂)_(m)—SO₂—NH₂,(CH₂)_(m)—SO₂—NH—(C₁—C₆)-alkyl, (CH₂)_(m)—SO₂—N[(C₁—C₆)-alkyl]₂ or(CH₂)_(m)—SO₂—N(═CH—N(CH₃)₂), wherein m is 0-6;

[0046] and R5 may be further substituted by F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁—C₆)-alkyl, S—(C₁—C₆)-alkyl, SO—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl,(C₃—C₆)-cycloalkyl, COOH, COO(C₁—C₆)-alkyl, COO(C₃—C₆)-cycloalkyl,CONH₂, CONH(C₁—C₆)-alkyl, CON[(C₁—C₆)-alkyl]₂, CONH(C₃—C₆)-cycloalkyl,NH₂, NH—CO—(C₁—C₆)-alkyl, NH—CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl,piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin- 1-yl,(CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl orSO₂—(CH₂)_(n)-phenyl, wherein n is 0-3;

[0047] and their physiologically acceptable salts and physiologicallyfunctional derivatives.

[0048] In a preferred embodiment, the compounds of formula I are where

[0049] R1, R1′ are independently selected from H, F, Cl, Br, I, CF₃,NO₂, CN, COOH, COO(C₁—C₆)-alkyl, CONH₂, CONH(C₁—C₆)-alkyl,CON[(C₁—C₆)-alkyl]₂, (C₁—C₆)-alkyl, (C₂—C₆)-alkenyl, (C₂—C₆)-alkynyl,O—(C₁—C₆)-alkyl,

[0050] wherein one hydrogen of the alkyl radicals may be replaced by OH,OC(O)CH₃, OC(O)H, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂;

[0051] SO₂—NH₂, SO₂NH(C₁—C₆)-alkyl, SO₂N[(C₁—C₆)-alkyl]₂,S—(C₁—C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁—C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂—(C₁—C₆)-alkyl, SO₂—(CH₂)_(n)-phenyl,

[0052] wherein n is 0-6 and the phenyl radical may be substituted up totwo times by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁—C₆)-alkyl,(C₁—C₆)-alkyl or NH₂;

[0053] NH₂, NH—(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂, NH(C₁—C₇)-acyl, phenyl,biphenylyl, O—(CH₂)_(n)-phenyl, wherein n is 0-6, 1- or 2-naphthyl, 2-,3- or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl

[0054] wherein any of the phenyl, biphenylyl, naphthyl, pyridyl, furanylor thienyl rings may be substituted one to 3 times by F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂,NH(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂, SO₂—CH₃, COOH, COO—(C₁—C₆)-alkyl orCONH₂;

[0055] 1,2,3-triazol-5-yl, where the triazole ring may be substituted inthe 1-, 2-or 3-position by methyl or benzyl; or

[0056] tetrazol-5-yl, where the tetrazole ring may be substituted in the1- or 2-position by methyl or benzyl;

[0057] R2 is H, (C₁—C₆)-alkyl, (C₃—C₆)-cycloalkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl,C(O)—(C₁—C₆)-alkyl, C(O)—(C₃—C₆)-cycloalkyl, C(O)—(CH₂)_(n)-phenyl,C(O)—(CH₂)_(n)-thienyl, C(O)—(CH₂)_(n)-pyridyl or C(O)—(CH₂)_(n)-furyl,

[0058] wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl andfuryl may be substituted up to two times by Cl, F, CN, CF₃,(C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;

[0059] R3 is H, (C₁—C₆)-alkyl, F, CN, N₃, O—(C₁—C₆)-alkyl,(CH₂)_(n)-phenyl, (CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl,

[0060] wherein n is 0-5 and in which any of phenyl, thienyl, pyridyl andfuryl may be substituted up to two times by Cl, F, CN, CF₃,(C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;

[0061] OC(O)CH₃, (C₂—C₆)-alkynyl, (C₂—C₆)-alkenyl, COO(C₁—C₆)-alkyl,C(O)OH, C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂;

[0062] R4 is (CH₂)_(n)—R5, wherein n is 0-6;

[0063] R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridylor 2- or 3-thienyl;

[0064] and R5 is substituted by NH—SO₂—(C₁—C₆)-alkyl, NH—SO₂-phenyl,

[0065] wherein the phenyl ring may be substituted up to two times by F,Cl, CN, OH, (C₁—C₆)-alkyl, O—(C₁—C₆)-alkyl, CF₃, COOH, COO(C₁—C₆)-alkyl,CONH₂;

[0066] (CH₂)_(n)—SO₂—(C₁—C₆)-alkyl, wherein n is 1-6, (CH₂)_(m)—SO₂—NH₂, (CH₂)_(m)—SO₂—NH—(C₁—C₆)-alkyl, (CH₂)_(m)—SO₂—N[(C₁—C₆]-alkyl)₂ or(CH₂)_(m)—SO₂—N(═CH—N(CH₃)₂), wherein m is 0-6;

[0067] and R5 may be further substituted by F, Cl, Br, OH, CF₃, CN,OCF₃, O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, (C₃—C₆)-cycloalkyl, COOH,COO(C₁—C₆)-alkyl, COO(C₃—C₆)-cycloalkyl, CONH₂, CONH(C₁—C₆)-alkyl,CON[(C₁—C₆)-alkyl]₂, NH₂, NH—CO—(C₁—C₆)-alkyl, NH—CO-phenyl,(CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl,SO₂—(CH₂)_(n)-phenyl, wherein n is 0-3;

[0068] and their physiologically acceptable salts and physiologicallyfunctional derivatives.

[0069] In a particularly preferred embodiment, the compounds of formulaI are where

[0070] R1, R1′ are independently selected from H, F, Cl, Br, I, CF3,NO₂, CN, COOH, COO(C₁—C₆)-alkyl, CONH₂, (C₁—C₆)-alkyl, (C₂—C₆)-alkenyl,(C₂—C₆)-alkynyl, O—(C₁—C₆)-alkyl, SO₂—NH₂, phenyl or O—(CH₂)_(n)-phenyl,

[0071] wherein n is 0-6, wherein any of the phenyl rings may besubstituted one to 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂ or CONH₂;

[0072] R2 is H, (C₁—C₆)-alkyl, (C₃—C₆)-cycloalkyl, (CH₂)_(n)-phenyl,C(O)—(C₁—C₆)-alkyl or C(O)—(CH₂)_(n)-phenyl,

[0073] wherein n is 0-5 and in which phenyl may be substituted up to twotimes by Cl, F, CN, CF₃, (C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;

[0074] R3 is H, (C₁—C₆)-alkyl, F, (CH₂)_(n)-phenyl,

[0075] wherein n is 0-5 and in which phenyl may be substituted up to twotimes by Cl, F, CN, CF₃, (C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;

[0076] COO(C₁—C₆)-alkyl, C(O)OH or C(O)NH₂;

[0077] R4 is (CH₂)_(n)—R5, wherein n is 0-6; or

[0078] R5 is phenyl, 1- or 2-naphthyl;

[0079] and R5 is substituted by NH—SO₂—(C₁—C₆)-alkyl, NH—SO₂-phenyl,

[0080] wherein the phenyl ring may be substituted up to two times by F,Cl, CN, OH, (C₁—C₆)-alkyl, O—(C₁—C₆)-alkyl, CF₃, COOH, COO(C₁—C₆)-alkylor CONH₂;

[0081] (CH₂)_(n)—SO₂—(C₁—C₆)-alkyl,

[0082] wherein n is 1-6,

[0083] (CH₂)_(m)—SO₂—NH₂, (CH₂)_(m)—SO₂—NH—(C₁—C₆)-alkyl,(CH₂)_(m)—SO₂—N[(C₁—C₆)-alkyl]₂ or (CH₂)_(m)—SO₂—N(═CH—N(CH₃)₂),

[0084] wherein m is 0-6;

[0085] and R5 may further be substituted by F, Cl, Br, OH, CF₃, CN,OCF₃, O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, COOH, COO(C₁—C₆)-alkyl, CONH₂,NH₂, NH—CO—(C₁—C₆)-alkyl, NH—CO-phenyl, (CH₂)_(n)-phenyl,O—(CH₂)_(n)-phenyl or SO₂—(CH₂)_(n)-phenyl,

[0086] wherein n is 0-3;

[0087] and their physiologically acceptable salts.

[0088] The invention relates to compounds of formula I, in the form oftheir racemates, racemic mixtures and pure enantiomers, and to theirdiastereomers and mixtures thereof.

[0089] The alkyl, alkenyl and alkynyl radicals in the substituents R1,R1′, R2, R3 and R5 may be either straight-chain or branched.

[0090] Pharmaceutically acceptable salts are particularly suitable formedicinal applications compared with the starting materials or basecompounds, due to their higher water solubility. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds according to theinvention are salts of inorganic acids, such as hydrochloric acid,hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid,sulfonic acid and sulfuric acid, and of organic acids, such as, forexample, acetic acid, benzenesulfonic acid, benzoic acid, citric acid,ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid,isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid,methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaricacid and trifluoroacetic acid. For medicinal purposes, the chlorine saltis particularly preferred. Suitable pharmaceutically acceptable basicsalts are ammonium salts, alkali metal salts (such as sodium salts andpotassium salts) and alkaline earth metal salts (such as magnesium saltsand calcium salts).

[0091] Salts having a pharmaceutically unacceptable anion are likewiseincluded in the scope of the invention as useful intermediates for theproduction or purification of pharmaceutically acceptable salts and/orfor use in nontherapeutic, for example in-vitro, applications.

[0092] The term “physiologically functional derivative” used hererelates to any physiologically acceptable derivative of a compound offormula I according to the invention, for example an ester, which, onadministration to a mammal, such as, for example, man, is able (directlyor indirectly) to form a compound of formula I or an active metabolitethereof.

[0093] The physiologically functional derivatives also include prodrugsof the compounds according to the invention. Such prodrugs are able tobe metabolized in vivo to a compound according to the invention. Theseprodrugs can themselves be active or inactive.

[0094] The compounds according to the invention may also be present invarious polymorphic forms, for example as amorphous and crystallinepolymorphic forms. All polymorphic forms of the compounds according tothe invention are included in the scope of the invention and are afurther aspect of the invention.

[0095] Hereinbelow, all references to “compound(s) according to formula(I)” refer to compounds of formula (I) as described above, and to theirsalts, solvates and physiologically functional derivatives as describedherein.

[0096] The amount of a compound according to formula (I) which isnecessary in order to achieve the desired biological effect is dependenton a number of factors, for example the specific compound selected, theintended use, the manner of administration and the clinical condition ofthe patient. In general, the daily dose is in the range from 0.3 mg to100 mg (typically from 3 mg to 50 mg) per day per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, forexample, in the range from 0.3 mg to 1.0 mg/kg, which may be suitablyadministered as an infusion of 10 ng to 100 ng per kilogram per minute.Suitable infusion solutions for these purposes may contain, for example,from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.Individual doses may contain, for example, from 1 mg to 10 g of theactive compound. Thus, ampoules for injections may contain, for example,from 1 mg to 100 mg, and orally administrable individual doseformulations, such as, for example, tablets or capsules, may contain,for example, from 1.0 to 1 000 mg, typically from 10 to 600 mg. In thecase of pharmaceutically acceptable salts, the abovementioned weightdetails relate to the weight of the dihydrothiazolium ion derived fromthe salt. For the prophylaxis or therapy of the abovementionedconditions, the compounds according to formula (I) may be usedthemselves as the compound, but they are preferably present in the formof a pharmaceutical composition with a tolerable excipient. Theexcipient must of course be tolerable, in the sense that it iscompatible with the other constituents of the composition and is notharmful to the patient's health. The excipient may be a solid or aliquid or both and is preferably formulated with the compound as anindividual dose, for example as a tablet which may contain from 0.05% to95% by weight of the active compound. Further pharmaceutically activesubstances may also be present, including further compounds according toformula (I). The pharmaceutical compositions according to the inventionmay be prepared by one of the known pharmaceutical methods, whichessentially consist in mixing the constituents with pharmacologicallyacceptable excipients and/or auxiliaries.

[0097] Pharmaceutical compositions according to the invention are thosewhich are suitable for oral, rectal, topical, peroral (e.g. sublingual)and parenteral (e.g. subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable manner ofadministration in each individual case is dependent on the nature andseverity of the condition to be treated and on the nature of thecompound according to formula (I) used in each case. Sugar-coatedformulations and sugar-coated delayed release formulations are alsoincluded in the scope of the invention. Acid-resistant and entericformulations are preferred. Suitable enteric coatings include celluloseacetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0098] Suitable pharmaceutical compounds for oral administration may bepresent in separate units, such as, for example, capsules, cachets,lozenges or tablets which in each case contain a certain amount of thecompound according to formula (I); as powders or granules; as solutionor suspension in an aqueous or nonaqueous liquid; or as an oil-in-wateror water-in-oil emulsion. As already mentioned, these compositions maybe prepared by any suitable pharmaceutical method which includes a stepin which the active compound and the excipient (which may consist of oneor more additional constituents) are brought into contact. In general,the compositions are prepared by uniform and homogeneous mixing of theactive compound with a liquid and/or finely divided solid excipient,after which the product is shaped, if necessary. Thus a tablet, forexample, may be prepared by pressing or shaping a powder or granules ofthe compound, if appropriate with one or more additional constituents.Pressed tablets may be prepared by tableting the compound infree-flowing form, such as, for example, in a powder or granules, ifappropriate mixed with a binder, lubricant, inert diluent and/or one (anumber of) surface-active/dispersing agent(s) in a suitable machine.Shaped tablets may be prepared by shaping the pulverulent compound,moistened with an inert liquid diluent, in a suitable machine.

[0099] Pharmaceutical compositions which are suitable for peroral(sublingual) administration include lozenges which contain a compoundaccording to formula (I) with a flavoring, customarily sucrose and gumarabic or tragacanth, and pastilles which include the compound in aninert base such as gelatin and glycerol or sucrose and gum arabic.

[0100] Suitable pharmaceutical compositions for parenteraladministration preferably include sterile aqueous preparations of acompound according to formula (I), which are preferably isotonic withthe blood of the intended recipient. These preparations are preferablyadministered intravenously, although the administration may also takeplace subcutaneously, intramuscularly or intradermally as an injection.These preparations may preferably be prepared by mixing the compoundwith water and rendering the obtained solution sterile and isotonic withthe blood. Injectable compositions according to the invention in generalcontain from 0.1 to 5% by weight of the active compound.

[0101] Suitable pharmaceutical compositions for rectal administrationare preferably present as individual dose suppositories. These may beprepared by mixing a compound according to formula (I) with one or moreconventional solid excipients, for example cocoa butter, and shaping theresulting mixture.

[0102] Suitable pharmaceutical compositions for topical application tothe skin are preferably present as ointment, cream, lotion, paste,spray, aerosol or oil. Excipients which may be used are petroleum jelly,lanolin, polyethylene glycols, alcohols and combinations of two or moreof these substances. The active compound is in general present in aconcentration of from 0.1 to 15%, for example of from 0.5 to 2%, byweight of the composition.

[0103] Transdermal administration is also possible. Suitablepharmaceutical compositions for transdermal administration may bepresent as individual patches which are suitable for long-term closecontact with the epidermis of the patient. Such patches suitably containthe active compound in an optionally buffered aqueous solution,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active compound concentration is from about 1% to 35%,preferably from about 3% to 15%. As a particular possibility, the activecompound may be released by electrotransport or iontophoresis, asdescribed, for example, in Pharmaceutical Research, 2(6): 318 (1986).

[0104] The invention furthermore relates to a process for preparing thecompounds of formula I, which comprises obtaining the compounds offormula I in such a way that the procedure is according to the followingreaction scheme:

[0105] As part of the reaction scheme, compounds of formula II,

[0106] in which R1 and R1′ are as defined above, are reacted withbromine to give a compound of formula III in which R3 is as defined forformula I.

[0107] Compounds of formula III are then reacted with thioamides offormula IV

[0108] in which R4 is as defined for compounds of formula I in which R2is hydrogen, For their part, these compounds may be converted bystandard methods into compounds of formula I in which R2 is as definedfor formula I.

[0109] The compounds of formula I may also be present as salts withacids. Suitable inorganic acids are, for example: hydrohalic acids, suchas hydrochloric acid and hydrobromic acid, and also sulfuric acid,phosphoric acid and amidosulfonic acid. Organic acids which may bementioned are, for example: formic acid, acetic acid, benzoic acid,p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbicacid, salicylic acid, isethionic acid, methanesulfonic acid,trifluoromethanesulfonic acid, 1,2-benzisothiazol-3(2H)-one,6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.

[0110] In the reaction scheme described above, it is advantageous toreact the compounds of Formula III with the thioamides R4—C(S)—NH₂ in amolar ratio of from 1:1 to 1:1.5. The reaction is advantageously carriedout in an inert solvent, for example in polar organic solvents, such asdimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dioxane,tetrahydrofuran, acetonitrile, nitromethane or diethylene glycoldimethyl ether. Particularly advantageous solvents, however, have provedto be methyl acetate and ethyl acetate, short-chain alcohols, such asmethanol, ethanol, propanol, isopropanol, and lower dialkyl ketones,such as, for example, acetone, butan-2-one or hexan-2-one. Mixtures ofthe reaction media mentioned may also be used; and mixtures of thesolvents mentioned with solvents which, taken per se, are less suitable,such as, for example, mixtures of methanol with benzene, ethanol withtoluene, methanol with diethyl ether or with tert-butyl methyl ether,ethanol with carbon tetrachloride, acetone with chloroform,dichloromethane or 1,2-dichloroethane, may also be used, where the morepolar solvent in each case should be used in an excess. The reactantsmay be suspended or dissolved in the respective reaction medium. Inprinciple, the reactants may also be reacted in the absence of asolvent, in particular if the respective thioamide has a melting pointwhich is as low as possible. The reaction proceeds in an only slightlyexothermic manner and may be carried out between −10° C. and 150° C.,preferably between 30° C. and 100° C. A temperature range between 50° C.and 90° C. has generally been found to be particularly favorable.

[0111] The reaction time is largely dependent on the reactiontemperature and is between 2 minutes and 3 days at relatively high andrelatively low temperatures, respectively. In the favorable temperaturerange, the reaction time is generally between 5 minutes and 48 hours.

[0112] In the course of the reaction, the compounds of formula Ifrequently form a poorly soluble deposit in the form of their acidaddition salts, a suitable precipitating agent is additionallysubsequently added. Those used are, for example, hydrocarbons such asbenzene, toluene, cyclohexane or heptane or carbon tetrachloride; inparticular, alkyl acetates, such as ethyl acetate or n-butyl acetate, ordialkyl ethers, such as diethyl ether, diisopropyl ether, di-n-butylether or tert-butyl methyl ether prove particularly suitable. If thereaction mixture remains in solution after the end of the reaction, thesalts of the compounds of formula I may be precipitated using one of theprecipitating agents mentioned, if appropriate after concentration ofthe reaction solution. Furthermore, the solution of the reaction mixturemay also be advantageously filtered into the solution of one of theprecipitating agents mentioned, with stirring. Work-up of the reactionmixture may also be carried out such that the reaction mixture isrendered alkaline by addition of an organic base, such as, for example,triethylamine or diisobutylamine or ammonia or morpholine or piperidineor 1,8-diazabicyclo[5.4.0]undec-7-ene, and the crude reaction product ispurified chromatographically, for example on a silica gel column, afterconcentration. Suitable eluents for this prove to be, for example,mixtures of ethyl acetate with methanol, mixtures of dichloromethanewith methanol, mixtures of toluene with methanol or ethyl acetate ormixtures of ethyl acetate with hydrocarbons such as heptane. If thepurification of the crude product is carried out in the manner lastdescribed, an acid addition product of formula I may be obtained fromthe pure base of formula I thus obtained by dissolving or suspending thebase in an organic protic solvent, such as methanol, ethanol, propanolor isopropanol, or in an organic aprotic solvent, such as ethyl acetate,diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane,tetrahydrofuran, acetone or butan-2-one, and then treating this mixturewith an at least equimolar amount of an inorganic acid such as, forexample, hydrochloric acid, dissolved in an inert solvent such as, forexample, diethyl ether or ethanol, or another of the inorganic ororganic acids mentioned further above.

[0113] The compounds of formula I may be recrystallized from an inertsuitable solvent such as, for example, acetone, butan-2-one,acetonitrile or nitromethane. However, particularly advantageous is theprecipitation from a solvent such as, for example, dimethylformamide,dimethylacetamide, nitromethane, acetonitrile, preferably methanol orethanol.

[0114] The reaction of the compounds of formula III with the thioamidesof formula IV may also be carried out such that an at least equimolaramount of a base, such as, for example, triethylamine, is added to thereaction mixture and the resulting compounds I are then optionallyconverted into their acid addition products.

[0115] By treatment with bases, the acid addition products I may beconverted into the compounds of formula I (free base). Suitable basesare, for example, solutions of inorganic hydroxides, such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide orbarium hydroxide, carbonates or hydrogen carbonates, such as sodiumcarbonate or potassium carbonate, sodium hydrogen carbonate or potassiumhydrogen carbonate, ammonia and amines, such as triethylamine,diisopropylamine, dicyclohexylamine, piperidine, morpholine,methyldicyclohexylamine.

[0116] Thioamides of formula IV are either commercially available or maybe obtained, for example, by reaction of the corresponding carboxamidewith phosphorus pentasulfide in pyridine (R. N. Hurd, G. Delameter,Chem. Rev. 61, 45 (1961)), or with Lawesson's reagent in toluene,pyridine, hexamethylphosphoric triamide [Scheibye, Pedersen andLawesson: Bull. Soc. Chim. Belges 87, 229 (1978)], preferably in amixture of tetrahydrofuran with1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or1,3-dimethyl-2-imidazolidinone. Hydroxyl, amino or additional carbonylfunctions are in this case protected using a removable protectivefunction, such as, for example, a benzyl, tert-butyloxycarbonyl orbenzyloxycarbonyl radical, or converted into an optionally cyclicacetal. Methods for this are described, for example, in Th. W. Greeneand P. G. M. Wuts, Protective Groups in Organic Synthesis, SecondEdition, 1991, John Wiley & Sons, New York.

[0117] Thioamides of formula IV may also be obtained by reactingnitriles of formula VII

N≡C—R4  formula VII

[0118] with hydrogen sulfide (Houben-Weyl IX, 762) or thioacetamide (E.C. Taylor, J. A. Zoltewicz, J. Am. Chem. Soc. 82, 2656 (1960)) orO,O-diethyl dithiophosphoric acid. The reactions with hydrogen sulfideare preferably carried out in an organic solvent, such as methanol orethanol, those with thioacetamide in a solvent such as dimethylformamidewith addition of hydrochloric acid, and those with O,O-diethyldithiophosphoric acid in a solvent such as ethyl acetate under acidic,e.g. HCl, conditions at room temperature or with warming.

[0119] The examples given below serve to illustrate the invention, butwithout restricting it. The measured melting or decomposition points(m.p.) were not corrected and are generally dependent on the heatingrate. TABLE 1 Examples formula I

Example R1; R1′ R2 R3 R4 Salt m.p. [° C.] 1 6-Cl; H H H(C₆H₄)-4-NH—SO₂—(C₆H₄)-4-Cl — 116 2 6-Cl; H H H (C₆H₄)-4-(NH—SO₂—CH₃) —166 3 6-Cl; H H H (C₆H₃)-3-(SO₂—N═CH—N(CH₃)₂)-4-Cl — 180 4 6-Cl; H H H(C₆H₃)-3-(SO₂—NH₂)-4-Cl — 148 5 6-Cl; H H H (C₆H₄)-4-(SO₂—NH₂) — 160 6H; H H H (C₆H₄)-4-(SO₂—NH₂) HBr 250

[0120] The compounds of formula I are distinguished by favorable effectson lipid metabolism; in particular, they are suitable as anorectics.Other favorable effects on lipid metabolism include lowering cholesterolor low density lipoproteins (LDL) and increasing high densitylipoproteins (HDL). The compounds may be employed on their own or incombination with other anorectically active compounds. Such furtheranorectically active compounds are mentioned, for example, in the RoteListe, chapter 01 under slimming preparations/anorectics. Examplesinclude, but are not limited to, DECORPA© (From Pierre Fabre Pharma,common name, sterculia), XENIXAL© (from Rocher, common name, orlistat),ANTIADIPOSITUM X-112S (from Haenseler, common name,D-norpseudoephedrin-HCl), FASUPOND© (from Eu Tho Arzneil, common name,D-norpseudoephedrin-HCl), MIRAPRONT© (from Mack, Illert., common name,D-norpseudoephedrin-Poly(styrol, divinylbenzol) sulfonate), REGENONC©ι-retard (from Temmler Pharma, common name, Amfepramon-HCl), RONDIMEN©(from ASTA Medica AWD, common name, Mefenorex-HCl), TENUATE© Retard(from Artegodan, common name, Amfepramon-HCl), VITA-SCHLANKTROPFENSCHUCK (from Schuck, common name, D-norpseudoephedrine-HCl), VENCIPON©(from Artesan, common name, Ephedrin-HCL) CEFAMADAR© (from Cefak, commonname Nadar D4), and Helianthus tuberosus (Plantina). The compounds aresuitable for the prophylaxis and in particular for the treatment ofobesity. The compounds are furthermore suitable for the prophylaxis andin particular for the treatment of type II diabetes.

[0121] The efficacy of the compounds was tested as follows:

[0122] Biological Test Model

[0123] The anorectic action was tested on male or female NMRI mice.After withdrawal of feed for 24 hours, the test preparation wasadministered via a stomach tube. Kept individually and with free accessto drinking water, the animals were offered evaporated milk 30 minutesafter the administration of the preparation. The consumption ofevaporated milk was determined half-hourly for 3 hours and the generalcondition of the animals was observed. The measured milk consumption wascompared with that of untreated control animals. TABLE 2 Anorecticaction, measured as reduction of the cumulated milk consumption oftreated animals compared with untreated animals.

Oral dose [mg/kg] Number of animals/ cumulated milk consumption of thetreated animals N/[ml] Number of animals/ cumulated milk # consumptionof the untreated control animals N/[ml] Reduction of the cumulated milkconsumption in % of the control Example 4 50 female animals femaleanimals 69 5/0.82 5/2.66 Example 5 50 male animals male animals 955/0.08 5/1.54 Example 6 50 male animals male animals 76 5/1.26 5/5.10

[0124] The data in the above table indicate that the compounds offormula I exhibit very good anorectic action.

[0125] The preparation of some examples is described in detail below;the other compounds of formula I were obtained in a similar manner:

EXAMPLE 1 (Compound 1)

[0126]4-Cloro-N-[4-(6-Chloro-3a-Hydroxy-8,8a-Dihydro-3aH-Indeno[1,2-d]Thiazol-2-yl)-Phenyl]Benzenesulfonamide:

[0127] a) 2-Bromo-5-Chloroindan-1-One

[0128] 10 g (0.06 mol) of 5-chloroindan-1-one is dissolved with stirringat room temperature in 120 ml of glacial acetic acid. 0.05 ml of a 48%strength solution of HBr in water and then 3.074 ml (0.06 mol) ofbromine, dissolved in 25 ml of glacial acetic acid, are added dropwise.The reaction completed after 2 h of stirring at room temperature asdetermined by thin layer chromatography (TLC). The solution of the crudeproduct is, with stirring, slowly added dropwise to 300 ml of ice-water.The precipitated crude product is filtered off with suction and washedthoroughly with water. The moist residue is removed from the filterusing ethyl acetate, and the phases of the filtrate are separated. Theorganic phase is dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue is dissolved in 120 ml of hotn-heptane; the hot solution is filtered through a pleated filter and thesolution is then left to crystallize at 0° C. The crystallized productis filtered off with suction and dried under reduced pressure. M.P.:94-96° C.

[0129] b) 4-(4-Chlorobenzenesulfonylamino)Thiobenzamide

[0130] 0.26 g of 4-chloro-4′-cyanobenzenesulfonamide is suspended in 10ml of absolute ethanol and admixed with 0.15 ml of diethyldithiophosphate, and the mixture is stirred under reflux for 8 h.Another portion of 0.15 ml of diethyl dithiophosphate is then added, andthe mixture is stirred at reflux temperature for a further 12 h. Thecooled reaction mixture is concentrated under reduced pressure; theresidue is stirred with dichloromethane and the solid residue isfiltered off with suction, washed with dichloromethane and dried underreduced pressure. The resulting4-(4-chlorobenzenesulfonylamino)thiobenzamide is used for the next stepwithout any further purification.

[0131] c) 4-Chloro-N-[4-(6-Chloro-3a-Hydroxy-8,8a-Dihydro-3aH-Indeno[1,2-d]Thiazol-2-yl)Phenyl]Benzenesulfonamide

[0132] At room temperature, 0.15 g of the compound from Example 1b and0.11 g of the compound from Example 1a are dissolved in 5 ml of dryacetone, and the mixture is then stirred at room temperature for 4 h. 65μl of triethylamine are added, and the mixture is stirred at roomtemperature overnight. Another 20 μl of triethylamine are added, and themixture is stirred at room temperature for another night. The reactionmixture is then concentrated under reduced pressure; the residue isdissolved in ethyl acetate, washed twice with water and once with sat.sodium chloride solution, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue is purified by silicagel chromatography using toluene/acetone 3/1. This gives4-chloro-N-[4-(6-chloro-3a-hydroxy-8,8a-dihydro-3aH-indeno[1,2-d]thiazol-2yl)phenyl]benzenesulfonamide of melting point 116° C.

EXAMPLE 2 (Compound 6)

[0133]4-(6-Chloro-3a-hydroxy-8,8a-dihydro-3aH-indeno[1,2-d]thiazol-2-yl)benzenesulfonamideis prepared in a similar manner by reacting 2-bromo-5-chloroindan-1-onewith 4-sulfamoylthiobenzamide. The compound has a melting point of 160°C.

What is claimed is:
 1. A compound of formula I

in which R1, R1′ are independently selected from H, F, Cl, Br, I, CF₃,NO₂, CN, COOH, COO(C₁—C₆)-alkyl, CONH₂, CONH(C₁—C₆)-alkyl,CON[(C₁—C₆)-alkyl]₂, (C₁—C₆)-alkyl, (C₂—C₆)-alkenyl, (C₂—C₆)-alkynyl,O—(C₁—C₆)-alkyl, wherein one or more of the hydrogens of the alkylradicals may be replaced by fluorine, or one hydrogen may be replaced byOH, OC(O)CH₃, OC(O)H, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂; SO₂—NH₂,SO₂NH(C₁—C₆)-alkyl, SO₂N[(C₁—C₆)-alkyl]₂, S—(C₁—C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁—C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁—C₆)-alkyl, SO₂—(CH₂)_(n)-phenyl, wherein n is 0-6 and the phenylradical may be substituted up to two times by F, Cl, Br, OH, CF₃, NO₂,CN, OCF₃, O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl or NH₂; NH₂, NH—(C₁—C₆)-alkyl,N[(C₁—C₆)-alkyl]₂, NH(C₁—C₇)-acyl, phenyl, biphenylyl,O—(CH₂)_(n)-phenyl, where n is 0-6, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, wherein any of thephenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may besubstituted one to three times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂, NH(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂,SO₂—CH₃, COOH, COO—(C₁—C₆)-alkyl or CONH₂; 1,2,3-triazol-5-yl, where thetriazole ring may be substituted in the 1-, 2- or 3-position by methylor benzyl; or tetrazol-5-yl, where the tetrazole ring can be substitutedin the 1- or 2-position by methyl or benzyl; R2 is H, (C₁—C₆)-alkyl,(C₃—C₆)-cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-thienyl,(CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl, C(O)—(C₁—C₆)-alkyl,C(O)—(C₃—C₆)-cycloalkyl, C(O)—(CH₂)_(n)-phenyl, C(O)—(CH₂)_(n)-thienyl,C(O)—(CH₂)_(n)-pyridyl or C(O)—(CH₂)_(n)-furyl, wherein n is 0-5 and inwhich phenyl, thienyl, pyridyl and furyl may be substituted up to twotimes by Cl, F, CN, CF₃, (C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl; R3 is H,(C₁—C₆)-alkyl, F, CN, N₃, O—(C₁—C₆)-alkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl (CH₂)_(n)-furyl, wherein n is 0-5and in which phenyl, thienyl, pyridyl and furyl may be substituted up totwo times by Cl, F, CN, CF₃, (C₁—C₃)-alkyl, OH or O—(C₁—C₆)-alkyl;OC(O)CH₃, (C₂—C₆)-alkynyl, (C₂—C₆)-alkenyl, COO(C₁—C₆)-alkyl, C(O)OH,C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂; R4 is (CH₂)_(n)—R5, wherein n is 0-6;R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl,1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2- or 3-pyridazinyl,2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-(1,3,5-triazinyl), 2- or5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl, indol-5-yl orN-methylimidazol-2-, -4- or -5-yl; and R5 is substituted byNH—SO₂—(C₁—C₆)-alkyl or NH—SO₂-phenyl, wherein the phenyl ring may besubstituted up to two times by F, Cl, CN, OH, (C₁—C₆)-alkyl,O—(C₁—C₆)-alkyl, CF₃, COOH, COO(C₁—C₆)-alkyl, CONH₂,(CH₂)_(n)—SO₂—(C₁—C₆)-alkyl, wherein n is 1-6, (CH₂)_(m)—SO₂—NH₂,(CH₂)_(m)—SO₂—NH—(C₁—C₆)-alkyl, (CH₂)_(m)—SO₂—N[(C₁—C₆)-alkyl]₂ or(CH₂)_(m)—SO₂—N(═CH—N(CH₃)₂), wherein m is 0-6; and R5 may be furthersubstituted by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁—C₆)-alkyl,S—(C₁—C₆)-alkyl, SO—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, (C₃—C₆)-cycloalkyl,COOH, COO(C₁—C₆)-alkyl, COO(C₃—C₆)-cycloalkyl, CONH₂, CONH(C₁—C₆)-alkyl,CON[(C₁—C₆)-alkyl]₂, CONH(C₃—C₆)-cycloalkyl, NH₂, NH—CO—(C₁—C₆)-alkyl,NH—CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl,piperazin-1-yl, 4-methylpiperazin-1-yl, (CH₂)_(n)-phenyl,O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl, SO₂—(CH₂)_(n)-phenyl, wherein nis 0-3; and its physiologically acceptable salts and physiologicallyfunctional derivatives.
 2. The compound of claim 1 , wherein R1, R′ areindependently selected from H, F, Cl, Br, I, CF₃, NO₂, CN, COOH,COO(C₁—C₆)-alkyl, CONH₂, CONH(C₁—C₆)-alkyl, CON[(C₁—C₆)-alkyl]₂,(C₁—C₆)-alkyl, (C₂—C₆)-alkenyl, (C₂—C₆)-alkynyl, O—(C₁—C₆)-alkyl,wherein one hydrogen of the alkyl radicals may be replaced by OH,OC(O)CH₃, OC(O)H, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂; SO₂—NH₂,SO₂NH(C₁—C₆)-alkyl, SO₂N[(C₁—C₆)-alkyl]₂, S—(C₁—C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁—C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁—C₆)-alkyl, SO₂—(CH₂)_(n)-phenyl, wherein n is 0-6 and the phenylradical may be substituted up to two times by F, Cl, Br, OH, CF₃, NO₂,CN, OCF₃, O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂; NH₂, NH—(C₁—C₆)-alkyl,N[(C₁—C₆)-alkyl]₂, NH(C₁—C₇)-acyl, phenyl, biphenylyl,O—(CH₂)_(n)-phenyl, wherein n is 0-6, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl where the phenyl,biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings can in each casebe substituted one to 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂, NH(C₁—C₆)-alkyl, N[(C₁—C₆)-alkyl]₂,SO₂—CH₃, COOH, COO—(C₁—C₆)-alkyl, CONH₂; 1,2,3-triazol-5-yl, where thetriazole ring can be substituted in the 1-, 2- or 3-position by methylor benzyl; or tetrazol-5-yl, where the tetrazole ring can be substitutedin the 1- or 2-position by methyl or benzyl; R2 is H, (C₁—C₆)-alkyl,(C₃—C₆)-cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-thienyl,(CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl, C(O)—(C₁—C₆)-alkyl,C(O)—(C₃—C₆)-cycloalkyl, C(O)—(CH₂)_(n)-phenyl, C(O)—(CH₂)_(n)-thienyl,C(O)—(CH₂)_(n)-pyridyl or C(O)—(CH₂)_(n)-furyl, wherein n is 0-5 and inwhich phenyl, thienyl, pyridyl and furyl may be substituted up to twotimes by Cl, F, CN, CF₃, (C₁—C₃)-alkyl, OH, O—(C₁—C₆)-alkyl; R3 is H,(C₁—C₆)-alkyl, F, CN, N₃, O—(C₁—C₆)-alkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-thienyl, (CH₂)_(n)-pyridyl, (CH₂)_(n)-furyl, wherein n is 0-5and in which phenyl, thienyl, pyridyl and furyl can in each case besubstituted up to two times by Cl, F, CN, CF₃, (C₁—C₃)-alkyl, OH,O—(C₁—C₆)-alkyl; OC(O)CH₃, (C₂—C₆)-alkynyl, (C₂—C₆)-alkenyl,COO(C₁—C₆)-alkyl, C(O)OH, C(O)NH₂, C(O)NHCH₃ or C(O)N(CH₃)₂; R4 is(CH₂)_(n)—R5, wherein n is 0-6; R5 is phenyl, biphenylyl, 1- or2-naphthyl, 2-, 3- or 4-pyridyl or 2- or 3-thienyl; and R5 issubstituted by NH—SO₂—(C₁—C₆)-alkyl, NH—SO₂-phenyl, wherein the phenylring may be substituted up to two times by F, Cl, CN, OH, (C₁—C₆)-alkyl,O—(C₁—C₆)-alkyl, CF₃, COOH, COO(C₁—C₆)-alkyl, CONH₂;(CH₂)_(n)—SO₂—(C₁—C₆)-alkyl, wherein n is 1-6, (CH₂)_(m)—SO₂NH₂,(CH₂)_(m)—SO₂—NH—(C₁—C₆)-alkyl, (CH₂)_(m)—SO₂—N[(C₁—C₆]-alkyl)₂ or(CH₂)_(m)—SO₂—N(═CH—N(CH₃)₂), wherein m is 0-6; and R5 may be furthersubstituted by F, Cl, Br, OH, CF₃, CN, OCF₃, O—(C₁—C₆)-alkyl,(C₁—C₆)-alkyl, (C₃—C₆)-cycloalkyl, COOH, COO(C₁—C₆)-alkyl,COO(C₃—C₆)-cycloalkyl, CONH₂, CONH(C₁—C₆)-alkyl, CON[(C₁—C₆)-alkyl]₂,NH₂, NH—CO—(C₁—C₆)-alkyl, NH—CO-phenyl, (CH₂)_(n)-phenyl,O—(CH₂)_(n)-phenyl, S—(CH₂)_(n)-phenyl, SO₂—(CH₂)_(n)-phenyl, wherein nis 0-3; and their physiologically acceptable salts and physiologicallyfunctional derivatives.
 3. The compound of claim 1 , wherein R1, R′ areindependently selected from H, F, Cl, Br, I, CF₃, NO₂, CN, COOH,COO(C₁—C₆)-alkyl, CONH₂, (C₁—C₆)-alkyl, (C₂—C₆)-alkenyl,(C₂—C₆)-alkynyl, O—(C₁—C₆)-alkyl, SO₂—NH₂, phenyl, O—(CH₂)_(n)-phenyl,wherein n is 0-6, wherein the phenyl rings can in each case besubstituted one to 3 times by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁—C₆)-alkyl, (C₁—C₆)-alkyl, NH₂, CONH₂; R2 is H, (C₁—C₆)-alkyl,(C₃—C₆)-cycloalkyl, (CH₂)_(n)-phenyl, C(O)—(C₁—C₆)-alkyl or C(O)—(CH₂)-phenyl, wherein n is 0-5 and in which phenyl can be substituted up totwo times by Cl, F, CN, CF₃, (C₁—C₃)-alkyl, OH, O—(C₁—C₆)-alkyl; R3 isH, (C₁—C₆)-alkyl, F, (CH₂)_(n)-phenyl, wherein n is 0-5 and in whichphenyl can be substituted up to two times by Cl, F, CN, CF₃,(C₁—C₃)-alkyl, OH, O—(C₁—C₆)-alkyl; COO(C₁—C₆)-alkyl, C(O)OH or C(O)NH₂;R4 is (CH₂)_(n)—R5, wherein n is 0-6; or R5 is phenyl, 1- or 2-naphthyl;and R5 is substituted by NH—SO₂—(C₁—C₆)-alkyl, NH—SO₂-phenyl, whereinthe phenyl ring can be substituted up to two times by F, Cl, CN, OH,(C₁—C₆)-alkyl, O—(C₁—C₆)-alkyl, CF₃, COOH, COO(C₁—C₆)-alkyl, CONH₂;(CH₂)_(n)—SO₂—(C₁—C₆)-alkyl, wherein n is 1-6, (CH₂)_(m)—SO₂—NH₂,(CH₂)_(m)—SO₂—NH—(C₁—C₆)-alkyl, (CH₂)_(m)—SO₂—N[(C₁—C₆)-alkyl]₂ or(CH₂)_(m)—SO₂—N(═CH—N(CH₃)₂), wherein m is 0-6; and R5 may further beubstituted by F, Cl, Br, OH, CF₃, CN, OCF₃, O—(C₁—C₆)-alkyl,(C₁—C₆)-alkyl, COOH, COO(C₁—C₆)-alkyl, CONH₂, NH₂, NH—CO—(C₁—C₆)-alkyl,NH—CO-phenyl, (CH₂)_(n)-phenyl, O—(CH₂)_(n)-phenyl,SO₂—(CH₂)_(n)-phenyl, wherein n is 0-3; and their physiologicallyacceptable salts.
 4. A pharmaceutical composition, comprising one ormore of the compounds as claimed in claim 1 .
 5. A pharmaceuticalcomposition, comprising one or more of the compounds as claimed in claim2 .
 6. A pharmaceutical composition, comprising one or more of thecompounds as claimed in claim 3 .
 7. A pharmaceutical composition,comprising one or more of the compounds as claimed in claim 1 , andfurther comprising one or more anorectic active ingredients.
 8. Apharmaceutical composition, comprising one or more of the compounds asclaimed in claim 2 , and further comprising one or more anorectic activeingredients.
 9. A pharmaceutical composition, comprising one or more ofthe compounds as claimed in claim 3 , and further comprising one or moreanorectic active ingredients.
 10. A method for the prophylaxis ortreatment of obesity comprising administering to a patient in need thereof one or more compounds as claimed in claim 1 .
 11. The method of claim10 , further comprising administering an additional anorectic activeagent.
 12. A method for the prophylaxis or treatment of obesitycomprising administering to a patient in need there of one or morecompounds as claimed in claim 2 .
 13. The method of claim 12 , furthercomprising administering an additional anorectic active agent.
 14. Amethod for the prophylaxis or treatment of obesity comprisingadministering to a patient in need there of one or more compounds asclaimed in claim 3 .
 15. The method of claim 14 , further comprisingadministering an additional anorectic active agent.
 16. A method for theprophylaxis or treatment of type II diabetes comprising administering toa patient in need there of one or more compounds as claimed in claim 1 .17. The method of claim 16 , further comprising administering anadditional anorectic active agent.
 18. A method for the prophylaxis ortreatment of type II diabetes comprising administering to a patient inneed there of one or more compounds as claimed in claim 2 .
 19. Themethod of claim 18 , further comprising administering an additionalanorectic active agent.
 20. A method for the prophylaxis or treatment oftype II diabetes comprising administering to a patient in need there ofone or more compounds as claimed in claim 3 .
 21. The method of claim 20, further comprising administering an additional anorectic active agent.22. A method for enhancing lipid metabolism comprising administering toa patient in need thereof one or more compounds as claimed in claim 1 .23. The method of claim 22 , further comprising administering anadditional anorectic active agent.
 24. A method for enhancing lipidmetabolism comprising administering to a patient in need thereof one ormore compounds as claimed in claim 2 .
 25. The method of claim 24 ,further comprising administering an additional anorectic active agent.26. A method for enhancing lipid metabolism comprising administering toa patient in need thereof one or more compounds as claimed in claim 3 .27. The method of claim 26 , further comprising administering anadditional anorectic active agent.
 28. A process for preparing apharmaceutical composition comprising one ore more of the compounds asclaimed in claim 1 , which comprises mixing the active compound with apharmaceutically suitable excipient and forming a composition suitablefor administration.
 29. A process for preparing a pharmaceuticalcomposition comprising one ore more of the compounds as claimed in claim2 , which comprises mixing the active compound with a pharmaceuticallysuitable excipient and forming a composition suitable foradministration.
 30. A process for preparing a pharmaceutical compositioncomprising one ore more of the compounds as claimed in claim 3 , whichcomprises mixing the active compound with a pharmaceutically suitableexcipient and forming a composition suitable for administration.
 31. Aprocess for preparing compounds as claimed in claim 1 , which comprisesreacting, according to the equation below,

a compound of formula II in which R1 and R1′ and R3 are as defined forformula I with bromine to give a compound III in which R1, R1′ and R3are as defined for formula I, and reacting the compound of formula IIIfurther with thioamides of formula IV in which R4 is as defined forformula I to give a compound to formula I.